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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Abstract : Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02430168
Contributor : Marie-Christine Vougny <>
Submitted on : Tuesday, January 7, 2020 - 10:36:53 AM
Last modification on : Tuesday, October 20, 2020 - 1:04:02 PM

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Christopher Duncan, Benjamin Thompson, Rui Chen, Gillian Rice, Florian Gothe, et al.. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Science Immunology, American Association for the Advancement of Science, 2019, 4 (42), pp.eaav7501. ⟨10.1126/sciimmunol.aav7501⟩. ⟨pasteur-02430168⟩

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